Title: Control of the cell cycle by mRNA degradation. Over the last period of this project we have extensively defined the role of the ribonucleoprotein endoribonuclease, RNase MRP, in mRNA degradation and cell cycle control. These studies have led us to discovering a new organelle, the TAM (Temporal Asymmetric MRP) body. We have found that this structure is P (processing) body "like". But in contrast to P bodies that are found throughout cells and the cell cycle, TAM bodies are temporally and spatially assembled organelles whose function is to degrade specific mRNAs at a discrete time and location in the cell cycle. P bodies or GW bodies have been implicated in regulating development, microRNAs and the cell cycle. RNase MRP is conserved throughout eukaryotes and mutations in the human RNA component have implicated this enzyme as an essential growth regulator. Human mutations cause Cartilage Hair Hypoplasia (CHH) a recessively inherited disorder characterized by short stature, brittle hair, anemia, immunodeficiency, and a predisposition to the development of lymphomas and other cancers. Data from our lab in collaboration with others has shown that human RNase MRP is also playing a role in destabilizing certain mRNAs. Failure to normally degrade certain mRNAs could easily cause the cell cycle delay seen in the human disease and the resulting phenotypes. Hence, these studies will have direct implications on human disease and pathogenesis. Experimentation will attack this problem in the yeast, Saccharomyces cerevisiae, an excellent RNase MRP model system that has proven to be highly conserved with the mammalian model systems. The specific aims have been designed to take advantages of the strengths in the yeast systems allowing us to learn more about RNase MRP, TAM bodies, and mRNA degradation. Our past history of using a simple genetic model system to lend insights into human disease considerably strengthens our proposal. In addition, our analysis of the molecular mechanism whereby complex genetic interactions lead to a phenotype and disease will provide much needed information as to how disease occurs in humans. PUBLIC HEALTH RELEVANCE: RNase MRP is conserved throughout eukaryotes and mutations in the human RNA component have implicated this enzyme as an essential growth regulator. Human mutations lead to Cartilage Hair Hypoplasia (CHH), a recessively inherited disorder characterized by short stature, brittle hair, anemia, immunodeficiency, and a predisposition to the development of lymphomas and other cancers. Based on our results from yeast it has already been shown that human RNase MRP is also playing a role in destabilizing certain mRNAs. This is data from our lab in collaboration with others. Failure to normally degrade certain mRNAs could easily cause the cell cycle delay seen in the human disease and the resulting phenotypes. Hence, these studies will have direct implications on human disease and pathogenesis. Over the last several years an immense amount has been learned about how cells control their division process. However the details and exact mechanism of many of the steps in the regulation of this process are still poorly understood. The incorrect regulation of cell division is the basis of all cancers. Understanding the details of how cell division is regulated and controlled is essential for controlling cancer and finding cures. RNase MRP is directly involved in the late stages of the cell division cycle by regulating mRNA levels of critical cell cycle molecules. The project will provide us with a better picture of how cells regulate the cell cycle and may provide some important new targets for antineoplastic agents.